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Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab
List of authors.- Anil Gupta, M.D.,
- Yaneicy Gonzalez-Rojas, M.D.,
- Erick Juarez, M.D.,
- Manuel Crespo Casal, M.D.,
- for the COMET-ICE Investigators*
Abstract
BACKGROUND
Coronavirus disease 2019 (Covid-19) disproportionately results in hospitalization or death in older patients and those with underlying conditions. Sotrovimab is a pan-sarbecovirus monoclonal antibody that was designed to prevent progression of Covid-19 in high-risk patients early in the course of disease.
METHODS
In this ongoing, multicenter, double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, nonhospitalized patients with symptomatic Covid-19 (≤5 days after the onset of symptoms) and at least one risk factor for disease progression to receive a single infusion of sotrovimab at a dose of 500 mg or placebo. The primary efficacy outcome was hospitalization (for >24 hours) for any cause or death within 29 days after randomization.
RESULTS
In this prespecified interim analysis, which included an intention-to-treat population of 583 patients (291 in the sotrovimab group and 292 in the placebo group), 3 patients (1%) in the sotrovimab group, as compared with 21 patients (7%) in the placebo group, had disease progression leading to hospitalization or death (relative risk reduction, 85%; 97.24% confidence interval, 44 to 96; P=0.002). In the placebo group, 5 patients were admitted to the intensive care unit, including 1 who died by day 29. Safety was assessed in 868 patients (430 in the sotrovimab group and 438 in the placebo group). Adverse events were reported by 17% of the patients in the sotrovimab group and 19% of those in the placebo group; serious adverse events were less common with sotrovimab than with placebo (in 2% and 6% of the patients, respectively).
CONCLUSIONS
Among high-risk patients with mild-to-moderate Covid-19, sotrovimab reduced the risk of disease progression. No safety signals were identified. (Funded by Vir Biotechnology and GlaxoSmithKline; COMET-ICE ClinicalTrials.gov number, NCT04545060. opens in new tab.)
Introduction
More than 4.8 million persons worldwide have died from coronavirus disease 2019 (Covid-19) during the global pandemic.1 In the United States alone, an estimated 960,000 to 2.4 million Covid-19–related hospitalizations occurred through the fall of 2020 and, at the peak of the pandemic in January 2021, 79% of hospital beds in intensive care units (ICUs) were occupied by patients with this disease.1-3 Older patients with Covid-19 and those with certain coexisting conditions such as obesity, diabetes mellitus, chronic obstructive pulmonary disease, and chronic kidney disease have been identified as being at highest risk for hospitalization or death.4-8
Highly effective therapeutic agents directed against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19, are needed for these high-risk persons. Recent data suggest that one option is monoclonal antibody therapy, which can reduce the risk of hospitalization9,10; however, the emergence and proliferation of SARS-CoV-2 variants that confer resistance to some antibodies are troubling.11,12 Furthermore, because additional variants of concern will probably continue to emerge, there is a great unmet need for therapeutic agents that, alone or in combination, can remain effective as the virus evolves. One possible solution is a monoclonal antibody that neutralizes SARS-CoV-2 by targeting an evolutionarily conserved epitope that lies outside the rapidly evolving receptor-binding motif. This antibody would be anticipated to have a high barrier to resistance, and because of its nonoverlapping resistance profile, it could be combined with receptor-binding motif–targeted antibodies when necessary to further heighten the barrier to resistance.
Sotrovimab, formerly known as VIR-7831, is an engineered human monoclonal antibody that neutralizes SARS-CoV-2 and multiple other sarbecoviruses, including SARS-CoV-1, the virus responsible for the SARS outbreak two decades ago.13 In fact, the parental form of sotrovimab, S309, was isolated from a patient with SARS-CoV-1.13 We hypothesized that a monoclonal antibody that neutralizes all sarbecoviruses would target a highly conserved epitope that would be functionally retained as SARS-CoV-2 evolves (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). Consistent with this hypothesis, we subsequently found that, in vitro, sotrovimab retained activity against variants of interest and concern, including the alpha, beta, gamma, delta, and lambda variants.11,14,15 In contrast, many of the other monoclonal antibodies under development for Covid-19 bind to the receptor-binding motif that engages the angiotensin-converting enzyme 2 (ACE2) receptor and is one of the most mutable and immunogenic regions of the virus; in some cases, these antibodies do not retain activity against the variants.16-19
Sotrovimab contains a two–amino acid Fc modification (termed LS) to increase half-life and potentially improve bioavailability in the respiratory mucosa through enhanced engagement with the neonatal Fc receptor.20-22This modification may permit therapeutic concentrations for longer durations.20-22Sotrovimab has been shown to have potent effector functions in vitro that may result in immune-mediated viral clearance.13,14
Here, we report the results of a prespecified interim analysis of the Covid-19 Monoclonal Antibody Efficacy Trial–Intent to Care Early (COMET-ICE), which was designed to evaluate the efficacy and safety of sotrovimab in high-risk, ambulatory patients with mild-to-moderate Covid-19. The trial is currently closed for enrollment; data collection is ongoing. Additional analyses of efficacy, safety, and laboratory data, as well as initial immunogenicity data, are under way.
Methods
TRIAL OBJECTIVES AND OVERSIGHT
In this phase 3, multicenter, randomized, double-blind, placebo-controlled trial, we evaluated a single intravenous infusion of sotrovimab at a dose of 500 mg for the prevention of progression of mild-to-moderate Covid-19 in high-risk, nonhospitalized patients. For this prespecified interim analysis, patients were recruited beginning on August 27, 2020, and were followed through March 4, 2021, at 37 trial sites in four countries (the United States, Canada, Brazil, and Spain). The protocol and statistical analysis plan are available at NEJM.org, and changes made to these documents after the trial began are summarized in the Supplementary Appendix.
The trial, which was sponsored by Vir Biotechnology in collaboration with GlaxoSmithKline, was conducted in accordance with the principles of the Declaration of Helsinki and the ethical guidelines of the Council for International Organizations of Medical Sciences, applicable International Council for Harmonisation Good Clinical Practice guidelines, and applicable laws and regulations. All the patients provided written informed consent. The sponsors designed the trial, and the sponsors and trial investigators participated in data collection, analysis, and interpretation. The authors made the decision to submit the manuscript for publication and vouch for the accuracy and completeness of the data presented and for the fidelity of the trial to the protocol. Medical writers who were funded by Vir Biotechnology assisted in drafting the manuscript under the authors’ direction. All the authors had confidentiality agreements with the sponsors.
PATIENTS AND PROCEDURES
Adult patients (≥18 years of age) who had a positive result on reverse-transcriptase–polymerase-chain-reaction or antigen SARS-CoV-2 testing and an onset of Covid-19 symptoms within the previous 5 days were screened for eligibility; screening was performed within 24 hours before the administration of sotrovimab or placebo. The patients were at high risk for progression of Covid-19 because of older age (≥55 years) or because they had at least one of the following risk factors: diabetes for which medication was warranted, obesity (body-mass index [BMI; the weight in kilograms divided by the square of the height in meters], >30), chronic kidney disease (estimated glomerular filtration rate, <60 ml per minute per 1.73 m2 of body-surface area),23 congestive heart failure (New York Heart Association class II, III, or IV), chronic obstructive pulmonary disease, and moderate-to-severe asthma.24 Patients with already severe Covid-19, defined as shortness of breath at rest, an oxygen saturation below 94%, or the use of supplemental oxygen, were excluded. Full inclusion and exclusion criteria are described in the Supplementary Methods section in the Supplementary Appendix.
Trial Design.Eligible patients were randomly assigned in a 1:1 ratio with the use of an interactive Web-based response system to receive either a single 500-mg, 1-hour infusion of sotrovimab or an equal volume of saline placebo on day 1 (Figure 1). The trial design did not mandate any treatment for Covid-19 other than sotrovimab or placebo; as a result, the patients received treatment at the discretion of their physicians according to the local standard of care.
EFFICACY ASSESSMENTS
The primary outcome was the percentage of patients who were hospitalized for more than 24 hours or who died from any cause through day 29 after randomization. Secondary efficacy outcomes included the percentage of patients with an emergency department visit, hospitalization, or death and the percentage of patients who had disease progression that warranted the use of supplemental oxygen.
SAFETY ASSESSMENTS
The safety outcomes included adverse events, serious adverse events, and adverse events of special interest, which were defined as infusion-related reactions (including hypersensitivity reactions). Immunogenicity testing for antidrug antibodies was performed, and antibody-dependent enhancement was evaluated. All hospitalizations, including those due to Covid-19, were counted as serious adverse events.
STATISTICAL ANALYSIS
A prespecified interim analysis for safety, futility, and efficacy was triggered when approximately 41% of the required number of trial patients reached day 29. Sample-size calculations were based on a group-sequential design with two interim analyses to assess both futility due to lack of efficacy and efficacy. A Lan–DeMets alpha-spending function was used to control type I error, with the use of a Pocock analogue rule for futility and a Hwang–Shih–DeCani analogue rule for efficacy (with the value of γ=1).25 The overall sample of 1360 patients would have provided approximately 90% power to detect a 37.5% relative efficacy in reducing progression of Covid-19 through day 29 at the overall two-sided 5% significance level, with an assumed incidence of progression of 16% in the placebo group.
In the interim analysis, the intention-to-treat population included all the patients who underwent randomization through the prespecified interim analysis cutoff date of January 19, 2021, irrespective of whether they received sotrovimab or placebo. The safety analysis population in the interim analysis included all the patients who received sotrovimab or placebo and underwent randomization through February 17, 2021; patients were grouped according to the actual agent received. The primary outcome was analyzed in the intention-to-treat population with the use of a Poisson regression model with robust sandwich estimators to adjust for trial agent, duration of symptoms, age, and sex. Missing progression status was imputed under a missing-at-random assumption with the use of multiple imputation. On the basis of this analysis model, the statistical significance testing, the relative risk of progression, and its appropriate confidence interval are provided with the adjusted significance level for this interim analysis.
An independent data monitoring committee recommended that enrollment in the trial be stopped on March 10, 2021, because of efficacy, at which time 1057 patients had undergone randomization. Analyses of all secondary and exploratory outcomes are planned when all the patients have completed day 29.
Results
PATIENTS
Of 795 patients who underwent screening, 583 underwent randomization by January 19, 2021, and were assigned to receive sotrovimab (291 patients) or placebo (292 patients); these patients composed the intention-to-treat population for the interim analysis (Fig. S2 and Table S1). In this intention-to-treat population, both the numbers of patients who withdrew from or continued in the trial and the durations of follow-up were similar in the two trial groups. Overall, 4 patients each in the sotrovimab and placebo groups withdrew from the trial (3 patients in the sotrovimab group withdrew before they received sotrovimab). The median duration of follow-up in the intention-to-treat population was 72 days (range, 5 to 190) in the sotrovimab group and 72 days (range, 16 to 190) in the placebo group.
Overall, 868 patients (430 patients in the sotrovimab group and 438 in the placebo group) underwent randomization and received sotrovimab or placebo by February 17, 2021; these patients composed the safety analysis population for the interim analysis. The median duration of follow-up in this population was 56 days (range, 5 to 190) in the sotrovimab group and 55 days (range, 2 to 190) in the placebo group.
Baseline Demographic and Disease Characteristics (Intention-to-Treat Population).In the intention-to-treat population, baseline demographic and disease characteristics were similar in the sotrovimab and placebo groups (Table 1). Overall, 22% of the patients were 65 years of age or older, 7% were Black, 63% were Hispanic or Latino, and 42% had two or more conditions that were considered to be risk factors for progression of Covid-19. The most common risk factors were obesity, an age of 55 years or older, and diabetes for which medication was warranted. The most common presenting symptoms (in ≥62% of all the patients) were cough, muscle aches or myalgia, headache, and fatigue (Table S2). Baseline demographic and disease characteristics in the safety analysis population were similar in the two trial groups and are reported in Table S3.
EFFICACY OUTCOMES
Efficacy Outcomes through Day 29 (Intention-to-Treat Population).
Primary Reasons for Hospitalization Longer than 24 Hours (Intention-to-Treat Population).A total of 3 of 291 patients in the sotrovimab group (1%), as compared with 21 of 292 patients in the placebo group (7%), had disease progression leading to hospitalization (for >24 hours) for any cause or death (relative risk reduction, 85%; 97.24% confidence interval [CI], 44 to 96; P=0.002) (Table 2). The primary reasons for the 24 hospitalizations were consistent with progressive Covid-19 (Table 3), with one probable exception: 1 patient in the sotrovimab group who had a notable medical history of small-intestinal obstruction presented 22 days after infusion with a small-intestinal obstruction.
All 5 patients who were admitted to the ICU were in the placebo group; 2 of these 5 patients received invasive mechanical ventilation, and a third patient declined to undergo intubation and subsequently died by day 29. Emergency department visits without hospitalization or hospitalization for less than 24 hours were observed in fewer patients in the sotrovimab group than in the placebo group (Table 2).
SAFETY
Adverse Events (Safety Analysis Population).In the safety analysis population, 73 of 430 patients in the sotrovimab group (17%) and 85 of 438 patients in the placebo group (19%) reported an adverse event (Table 4). The percentage of patients who reported grade 3 or 4 adverse events was lower in the sotrovimab group (2%) than in the placebo group (6%). Overall, the only adverse event that occurred in at least 1% of the patients who received sotrovimab was diarrhea, which occurred in 6 patients (1%) in the sotrovimab group (5 cases of diarrhea that were mild in severity and 1 case that was moderate in severity). Diarrhea occurred in 3 patients (<1%) in the placebo group.
The percentage of patients with infusion-related reactions was the same in the two groups (1% in each). One patient who received sotrovimab had an infusion-related reaction (moderate [grade 2] dyspnea) that was considered by the investigators to be related to sotrovimab.
Serious adverse events occurred in 2% of the patients who received sotrovimab and in 6% of those who received placebo. Most of these events were hospitalizations for Covid-19–related causes. No serious adverse events were considered by the investigators to be related to sotrovimab. One patient in the placebo group died after day 29; this patient died from Covid-19 pneumonia on day 37.
No trends were observed in hematologic values, liver-function values, or other laboratory data. Overall, laboratory results were similar in the sotrovimab and placebo groups.
Discussion
In this prespecified interim analysis of COMET-ICE involving high-risk adults with symptomatic Covid-19, the relative risk reduction in hospitalization (for >24 hours) or death between patients who received a single 500-mg dose of sotrovimab and those who received placebo was 85%. Among patients who were hospitalized, none of the patients who received sotrovimab were admitted to the ICU, as compared with five patients who received placebo; this finding suggests that sotrovimab prevented more severe complications of Covid-19 in addition to preventing hospitalization. Furthermore, as a result of investigator site selection, more than 60% of the trial population consisted of patients who identified as Hispanic or Latinx; thus, this trial showed efficacy in a population that has been underrepresented in clinical trials involving patients with Covid-19, despite the disproportionately negative effect that the pandemic has had on this ethnic group. Overall, no safety signals were identified in this trial. There was also no evidence of antibody-dependent enhancement with sotrovimab, which would have manifested as more patients with worsening of disease in the sotrovimab group than in the placebo group.26
Sotrovimab is a potential therapeutic agent in the fight against Covid-19, for which there remains an unmet medical need despite the recent success of preventative measures such as vaccines. Challenges associated with access to vaccines, vaccine hesitancy, medical contraindications to vaccines, immunocompromised persons who may not have a response to a vaccine, and most important, the potential emergence of variant viruses that escape vaccine-derived immunity, may all contribute to what is likely to be a large and enduring number of patients with Covid-19 for whom treatment is warranted.
Treatments for Covid-19 that retain activity even in the face of a rapidly evolving virus are needed. To that end, sotrovimab was selected to have an intrinsically higher barrier to resistance as a result of targeting a pan-sarbecovirus epitope.14In one analysis, among more than 1.7 million SARS-CoV-2 sequences in the Global Initiative on Sharing All Influenza Data database, amino acid positions composing the sotrovimab epitope were at least 99.8% conserved in naturally occurring viruses.14 Moreover, when necessary to further enhance breadth and barrier to resistance, sotrovimab can probably be combined with currently authorized receptor-binding motif–targeted antibodies because of its nonoverlapping resistance profile.
This interim analysis has several major limitations. First, with only three hospitalizations in the sotrovimab group, it is not possible to determine which patient or disease characteristics might be associated with sotrovimab treatment failure. Second, the number of patients in the sotrovimab group in the safety analysis population was modest (430 patients), and thus a rare adverse event (in <1% of the patients) may not have been observed, although one would not be expected because sotrovimab was derived from an antibody isolated from a patient who had recovered from SARS-CoV-1 infection, has minimal engineering, and targets a viral epitope (not a host epitope). Third, the presence of a baseline autologous antibody response to SARS-CoV-2 has not yet been analyzed to determine what effect emerging autologous immunity may have on the safety and efficacy of sotrovimab. Finally, secondary and exploratory outcome analyses were excluded from this interim analysis because the trial is ongoing; such analyses to further determine the potential additional benefits of sotrovimab are under way.
This trial has implications beyond showing the therapeutic value of sotrovimab. First, the results indicate that a single binding antibody against the non–receptor-binding motif, which does not directly block the ACE2 receptor interaction, can be clinically therapeutic, and thus the results suggest a role for other receptors.27 Second, because sotrovimab has potent effector function, the efficacy and absence of safety signals suggest that effector function is neither detrimental nor associated with antibody-dependent enhancement.26 In fact, preclinical models of Covid-19 suggest that the potent effector function of this agent may be beneficial.13,14
The results of this interim analysis of COMET-ICE indicate that sotrovimab can be a therapeutic agent for outpatients with Covid-19. Notably, a 500-mg dose may also permit intramuscular administration, which may increase the convenience of and access to therapeutic antibody agents for patients with Covid-19. Studies are currently under way to evaluate this route of administration. Given its in vitro activity against variants of interest and concern,14 as well as its ability to neutralize other sarbecoviruses, we speculate that sotrovimab has the potential to remain therapeutically active even as SARS-CoV-2 continues to evolve.
Funding and Disclosures
Supported by Vir Biotechnology and
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was published on October 27, 2021, at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
We thank Caryn Gordon, Pharm.D., and Courtney St. Amour, Ph.D., of Cello Health Communications–SciFluent for medical-writing support and Krystyna Grycz, B.A., Jordan Clark, B.S., and Minnie Kuo, M.S., of Vir Biotechnology for clinical operations support.
Author Affiliations
From the Albion Finch Medical Centre, William Osler Health Centre, Toronto (A.G.); Optimus U (Y.G.-R.) and Florida International Medical Research (E.J.), Miami, Pines Care Research Center, Pembroke Pines (J.M.), and Sarkis Clinical Trials, Gainesville (E.S.) — all in Florida; Álvaro Cunqueiro Hospital, IIS Galicia Sur, Vigo, Spain (M.C.C.); Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (D.R.F.); Centex Studies, McAllen (J. Solis), and Central Texas Clinical Research, Austin (C.B.) — both in Texas; Vir Biotechnology, San Francisco (H.Z., A.L.C., C.M.H., J. Sager, E.M., E.A., P.S.P., M.A.); GlaxoSmithKline, Stevenage, United Kingdom (N.S., C.T.); GlaxoSmithKline, Cambridge, MA (A.P.); Pinnacle Research Group, Anniston, AL (A.F.); and the Departments of Global Health and Medicine, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle (A.E.S.).
Dr. Shapiro can be contacted at aeshapir@uw.edu or at the Fred Hutchinson Cancer Research Center, Mailstop E5-110, 1100 Fairview Ave. N., Seattle, WA 98109.
A list of the COMET-ICE investigators is provided in the Supplementary Appendix, available at NEJM.org.
Supplementary Material
| Protocol | 4534KB | |
| Supplementary Appendix | 386KB | |
| Disclosure Forms | 1026KB | |
| Data Sharing Statement | 70KB |
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